Sedation depth and long-term mortality in mechanically ventilated critically ill adults: a prospective longitudinal multicentre cohort study

Abstract

Purpose: To ascertain the relationship among early (first 48 h) deep sedation, time to extubation, delirium and long-term mortality.

Methods: We conducted a multicentre prospective longitudinal cohort study in 11 Malaysian hospitals including medical/surgical patients (n = 259) who were sedated and ventilated ≥24 h. Patients were followed from ICU admission up to 28 days in ICU with 4-hourly sedation and daily delirium assessments and 180-day mortality. Deep sedation was defined as Richmond Agitation Sedation Score (RASS) ≤-3.

Results: The cohort had a mean (SD) age of 53.1 (15.9) years and APACHE II score of 21.3 (8.2) with hospital and 180-day mortality of 82 (31.7%) and 110/237 (46.4%). Patients were followed for 2,657 ICU days and underwent 13,836 RASS assessments. Midazolam prescription was predominant compared to propofol, given to 241 (93%) versus 72 (28%) patients (P < 0.0001) for 966 (39.6%) versus 183 (7.5%) study days respectively. Deep sedation occurred in (182/257) 71% patients at first assessment and in 159 (61%) patients and 1,658 (59%) of all RASS assessments at 48 h. Multivariable Cox proportional hazard regression analysis adjusting for a priori assigned covariates including sedative agents, diagnosis, age, APACHE II score, operative, elective, vasopressors and dialysis showed that early deep sedation was independently associated with longer time to extubation [hazard ratio (HR) 0.93, 95% confidence interval (CI) 0.89-0.97, P = 0.003], hospital death (HR 1.11, 95% CI 1.05-1.18, P < 0.001) and 180-day mortality (HR 1.09, 95% CI 1.04-1.15, P = 0.002), but not time to delirium (HR 0.98, P = 0.23). Delirium occurred in 114 (44%) of patients.

Conclusion: Irrespective of sedative choice, early deep sedation was independently associated with delayed extubation and higher mortality, and thus was a potentially modifiable risk in interventional trials.

Fig. 1

RASS assessments during early (first 48 h) and subsequent study days. During the first 48 h following initiation of mechanical ventilation, 2,859 RASS assessments were conducted, of which 58 % (1,658) were in the −3 to −5 range compared to 34 % (4,258/13,319) in the −2 to +1 range (P < 0.0001). There was a significant increase in the RASS score of 0 (Calm) after the first 48 h [(4,688/13,319) 35.2 % versus (323) 11.3 % (P < 0.0001) in the first 48 h]

Fig. 2

Kaplan-Meier curves for time to extubation. Time to extubation was significantly longer amongst patients who were deeply sedated early compared with those that were not. Median (IQR) time to extubation was 3.95 (2.7–6.9) versus 6.69 (4–11.7) days (log-rank P < 0.008)

Fig. 3

Kaplan-Meier curves for 180-day mortality. Those who were deeply sedated early (first 48 h) showed a significant increase in risk of death at 6 months (log-rank P = 0.001) compared with patients who were not deeply sedated